• Users Online: 365
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 254-263

Leptomeningeal metastasis from extracranial solid tumors


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission02-Feb-2020
Date of Decision21-Feb-2020
Date of Acceptance24-Feb-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Dr. Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_38_20

Get Permissions

  Abstract 


Background: Leptomeningeal metastasis (LM) is a dreaded complication associated with solid tumors which is increasing due to the advances in cancer-directed therapy. Proper diagnostic and treatment criteria are still not established for the handling of LM. This article aims to help outline a management plan for LM.
Methods: A systematic review of the articles on LM and solid tumors was done in PubMed for the past 15 years and eligible articles were eligible articles were considered. The articles related to hematological malignancies and brain tumors were excluded.
Results and Discussion: LM usually requires a strong suspicion based on the natural history of the disease and symptoms for diagnosis. Symptomatology, cerebrospinal fluid (CSF) examination, and magnetic resonance imaging aid in the diagnosis. The treatment involves a multimodal institution of intra-CSF therapy, systemic chemotherapy, craniospinal irradiation, and surgical interventions for relief of symptoms. The prognosis is usually poor despite treatment and expected survival is between 4 and 6 months.
Conclusion: The different options for the treatment of LM should be discussed in a multidisciplinary clinic. The treatment must be decided based on the neurological and general health condition of the patient, previous lines of treatment, and the presence of other metastatic sites. The improvement of levels of evidence for the various therapeutic procedures for patients with LM requires dedicated trials.

Keywords: Leptomeningeal metastasis, multidisciplinary clinic, prognosis, systematic review


How to cite this article:
Vallathol DH, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Leptomeningeal metastasis from extracranial solid tumors. Cancer Res Stat Treat 2020;3:254-63

How to cite this URL:
Vallathol DH, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Leptomeningeal metastasis from extracranial solid tumors. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jul 14];3:254-63. Available from: http://www.crstonline.com/text.asp?2020/3/2/254/287247




  Introduction Top


Leptomeningeal metastasis (LM) is due to the spread of cancer cells to the pia and arachnoid mater (which constitute the leptomeninges), subarachnoid space, and other cerebrospinal fluid (CSF) compartments.[1],[2] LM is seen in approximately 5%–10% of patients with solid cancer, usually related to progressive systemic spread during the course of disease. Improved diagnostic assessment and treatment have resulted in an increase in the occurrence of LM. The common extracranial solid tumors leading to LM are breast cancer, lung cancer, and melanoma.[3] Lately, new diagnostic methods and innovative targeted therapies have been developed that could potentially help with early diagnosis and improved treatment of LM. The main focus of this review article is LM secondary to solid primary cancers in adults, excluding those arising from the central nervous system (CNS) and hematological malignancies.


  Methods Top


A comprehensive systematic literature search in PubMed (Cochrane and Scopus) with keywords such as “Leptomeningeal Carcinomatosis AND Solid Tumors,” “Leptomeningeal Metastasis AND Solid tumors,” and “Neoplastic Meningitis AND solid tumors” was performed. [Figure 1] shows the flowchart followed for identification of articles for review.
Figure 1: Flowchart of the study selection process for the review of leptomeningeal metastases in patients with solid tumors

Click here to view



  Results and Discussion Top


Epidemiology and clinical features

Roughly 5%–10% of patients with solid tumors are clinically diagnosed with LM, but as shown by the autopsy series, the occurrence of undiagnosed or asymptomatic LM with many solid tumors may be 20% or more. Lung cancer, breast cancer, melanomas, gastrointestinal cancers, and carcinoma unknown primary are the most common solid tumors leading to LM.[4]

Resection of cerebellar parenchymal metastases has been reported to lead to the development of LM. The spillage of cancer cells directly into CSF followed by their dissemination is the assumed mechanism.[5],[6]

The use of more effective adjuvant and salvage systemic therapy is a significant factor leading to a heightened occurrence of LM, which also leads to a prolongation of survival and late metastatic spread to the CNS. The poor CNS penetration of novel targeted therapies is another reason leading to an increased occurrence of LM.[1],[4]

In patients with breast cancer, infiltrating lobular carcinoma and triple negative immunohistochemistry status are the factors that predispose to the development of LM.[7],[8]

Between 60% and 70% of patients also display progressive systemic disease during LM diagnosis.[9],[10] A duration of 1.2–2.0 years has been observed between the diagnosis of the malignancy and the diagnosis of LM in extracranial solid tumors.[11]

The location of involvement of the CNS dictates the symptoms and signs of the patients with LM. It relates to the signs and symptoms in the three domains of CNS functions, namely: (1) the cerebrum and its associated structures; (2) the cranial nerves; and (3) the spinal cord and spinal nerve roots. Cranial nerve and spinal nerve dysfunction, raised intracranial tension, or meningeal irritation are the common clinical findings.[12] The signs and symptoms in older patients are similar to those in younger patients; hence, the diagnosis does not differ.

Pathophysiology

Based on the histology of the primary tumor, cancer cells can enter the meninges via various pathways.

Even though malignant cell spread to the arachnoid through arterial circulation is the main reason for LM, it is seen less frequently in solid tumors when compared to hematological malignancies.[13]

Vertebral and paravertebral metastases could spread along the associated lymphatics or veins, or to the cranial nerves through the endoneural or perineural course or centripetally along the peripheral nerves.[14]

A direct spread has also been suggested for LM from the brain parenchyma.[15]

Diagnosis

As there are no tests that can categorically rule out the involvement of LM, the diagnosis remains challenging.

Cerebrospinal fluid examination

CSF examination is the most effective lab-based test for the identification of LM. Irregularities such as decreased glucose, raised protein concentration, increased leukocytes, and/or increased opening pressure, are suggestive of LM.[12]

Even though the identification of LM is generally confirmed by the presence of cancerous cells in the CSF, attributing it to a particular tumor is not possible.[16] Moreover, an early positive CSF cytology is only seen in 45%–55% of the patients with LM.[17]

Collection of at least 10.5 mL of non-hemorrhagic CSF sample from a site compatible with the clinical manifestations or directed by radiologic findings increases the sensitivity of CSF cytologic analysis. The collection of a second CSF sample in a similar manner improves the sensitivity of CSF cytology to 80% in patients with positive CSF.[18],[19]

Several biomarkers in the CSF aid in the earlier identification of LM and monitoring therapeutic response. Tumor markers, such as the carcinoembryonic antigen for adenocarcinomas, α-fetoprotein for hepatocellular and testicular tumors, and β-human chorionic gonadotropin for choriocarcinoma and testicular tumors, are somewhat specific for LM.[20],[21] Monitoring the levels of tumor markers also helps in the evaluation of response to treatment.

Techniques used for the detection of circulating tumor cells in the peripheral blood like NGS have shown promise when extrapolated to the CSF.[22],[23] Another technique that has proved to be useful in the identification of LM from solid tumors is the rare cell capture technology.[23] The new kid on the block, “liquid biopsy,” has also been used for diagnosis.[24]

The study of CSF flow dynamics with 111-In-diethyle netriaminepenta-acetic acid or 99Tc-macroaggregated albumin is suggested for LM and is useful to assess the CSF flow.[25],[26] Approximately 30%–70% of the patients with LM have displayed abnormal CSF circulation, with blocks commonly occurring at the skull base, the spinal canal, and over the cerebral gyri and sulci.[27],[28] Disturbed CSF flow in LM patients has been associated with a significantly reduced survival.[26],[29]

Neuroradiographic studies

In case of a clinical suspicion, magnetic resonance imaging (MRI) of the brain and spine is recommended which could detect leptomeningeal enhancement, which is often nodular and irregular.[30] If a lumbar puncture has been performed recently, imaging should be interpreted with proper care. The MRI sensitivity with gadolinium contrast is around 70%, and specificity is in the range of 77%–100%.[31] An abnormal MRI is sufficient to make the diagnosis in the presence of typical clinical features.[32] [Figure 2], [Figure 3], [Figure 4] show the typical appearance of LM on MRI imaging. [Figure 2] and [Figure 3] show the postcontrast T1-weighted image and [Figure 4] shows the postcontrast fluid-attenuated inversion recovery image depicting leptomeningeal enhancement.
Figure 2: T1-weighted postcontrast image showing leptomeningeal enhancement in a case of leptomeningeal metastasis

Click here to view
Figure 3: T1-weighted postcontrast image showing leptomeningeal enhancement in a case of leptomeningeal metastasis

Click here to view
Figure 4: Postcontrast fluid-attenuated inversion recovery sequence images showing leptomeningeal enhancement in a case of leptomeningeal metastasis

Click here to view


Prognosis

Despite the progress made in cancer management, the survival rate for patients with LM is still low. If treated, the overall survival (OS) from the time of diagnosis is approximately 2–4 months.[1] Progressive neurologic deterioration leads to death in untreated cases in 4–6 weeks.[11],[33] A Karnofsky Perfomance Status (KPS) >70, chemosensitivity of the primary malignancy, unimpaired CSF flow, CSF protein less than 50 mg/dL, and the administration of active disease control measures have been identified as favorable prognostic factors.[34]

Poor prognostic factors identified by the National Comprehensive Cancer Network are KPS <60, severe neurological deficits, widespread systemic disease with exhausted treatment options, bulky neurological disease, and encephalopathy.[35],[36]

The leading determinant of prognosis with regards to OS in LM is the type of primary cancer.[37],[38] Breast cancer LM has a relatively good prognosis compared to other solid tumors with a median OS ranging from 3.5–5 months.[39],[40] The survival of lung cancer-related LM has improved after the increased use of tyrosine kinase inhibitors (TKIs) and other targeted agents with a median survival of 3–4.3 months.[41]

Assessing response to therapy

It is challenging to evaluate the response to treatment. It is usually done in the clinics by clinical, radiologic, and CSF evaluation. The Response Assessment in Neuro-Oncology (RANO) Group proposed a standardized assessment in 2016 [Table 1] after realizing the difficulties in assessing outcomes.[42] The RANO criteria include imaging (usually MRI) of the brain and spine, a standard neurologic examination, and CSF evaluation. It is hoped that the criteria will be adopted as a new standard that can be included in future clinical trials to enable better assessment of the therapeutic response and comparisons across trials.
Table 1: Proposed Response Assessment in NeuroOncology (RANO) criteria for leptomeningeal metastasis in solid tumors

Click here to view


Symptom inventory

The RANO working group has provided a symptom inventory which includes complete standardized neurological examination [Table 2] and formal radiological assessment [Table 3].
Table 2: Neurological Examination used in the RANO criteria for a patient with leptomeningeal metastasis

Click here to view
Table 3: Radiographic assessment used in the RANO criteria for a patient with leptomeningeal metastasis

Click here to view


Treatment

Patients with LM who display progressive disease at other metastatic sites and those with limited treatment options and badly affected quality of life, due to irreversible neurologic deficits or encephalopathy, have a poor prognosis despite the use of aggressive LM-directed therapies. Such patients should probably be treated by a palliative approach.[12]

As most systemic chemotherapy drugs have limited capacity to cross the blood–brain barrier (BBB), they are usually combined with interventions such as radiation to prolong the survival, maintain the quality of file, and prevent the deterioration of neurologic function. Even though intra-CSF therapy is often considered the gold standard, meaningful clinical trial data from these efforts are lacking.[9]

Intrathecal chemotherapy

Rationale

The normal blood–brain barrier prevents the penetration of intravenously administered chemotherapeutic agents into the CNS. The intra-CSF chemotherapy acts via evasion of the blood–CSF barrier; this maximizes drug exposure in the CSF. This also causes less systemic chemotoxicity, which is a problem with intravenous administration. The lower volume of distribution of drugs in the CSF than that in the plasma ensures a higher drug concentration at a smaller dose. Most of the cytotoxic chemotherapy drugs have a longer t1/2 (halflife) in the CSF than in the plasma. This allows for prolonged CSF drug exposure. Cell cycle-specific chemotherapy agents such as methotrexate (MTX) and cytosine arabinoside (ara-C) are utilized for intra-CSF therapy due to this peculiarity. An equivalent volume of CSF (also known as isovolumetric withdrawal) should be removed before chemotherapy administration.[4]

Agents used and modes of administration

In routine daytoday practice, methotrexate, ara-C or liposomal ara-C, and thiotepa are utilized for intraventricular/intrathecal (IT) therapy.[4]

IT treatment is delivered by repeated lumbar punctures. Positional variation occurs with this procedure with respect to ventricular drug levels. Patients should therefore remain supine for at least one hour after IT drug injection. The Ommaya or Rickham reservoir is used in the intraventricular administration of drugs. Intraventricular reservoirs offer several advantages, including painless and relatively rapid time-efficient administration, and uniform drug distribution in the subarachnoid spaces and brain convexities.[4]

The impact of IT therapy on neurological outcomes and survival have been described in several retrospective studies.[43],[44] All the 5 randomized clinical trials [Table 4] conducted in patients with LM were concentrated on IT therapy. A limitation of the studies was that the patients who were determined to be too sick for treatment were excluded from most trials and series; which could have comprised a major proportion of patients at presentation. A study by Boogerd et al.[45] which included 35 patients with breast cancer, of which 17 were randomized to receive IT chemotherapy, and the rest to systemic chemotherapy, proved that neurologic response and survival were similar in the two arms; however, the trial accrued slowly, and was closed early. A retrospective study comprising 104 patients with LM compared patients who received systemic therapy and radiation with or without IT therapy for any solid tumor; no difference was observed in the median survival.[46] Quality-of-life measures were not reported in either study, and the patients who received IT chemotherapy had increased treatment-related neurotoxicity. IT glucocorticoids in combination with IT chemotherapy have not shown benefit in solid-tumor-associated LM compared to hematological malignancies.[9]
Table 4: Randomized trials of intrathecal chemotherapy in Leptomeningeal Metastasis from solid tumors

Click here to view


A therapeutic concentration of 1 mM/mL is achieved with a dose of 12-mg intra-CSF methotrexate and maintained for 48–72 h.[47],[48] The ideal regimen or schedule of IT MTX administration and duration of treatment is still not known. The median OS reported in retrospective studies ranges from 3.5 to 5 months. Folinic acid (leucovorin) rescue is not routinely advised except in cases of drug overdose.[39],[49],[50]

Ara-C is also used in IT therapy in LM similar to MTX. The low CSF cytidine deaminase leads to a much greater t1/2 of Ara-C in the CSF than in the serum.[4]

A depot formulation of Ara-C, called liposomal Ara-C, is frequently used. It solves the problem of the short t1/2 of AraC. Liposomal Ara-C has a t1/2 of 140 h and maintains a therapeutic concentration in the CSF for 10–12 days. Therefore, unlike the normal Ara-C, it needs to be administered once every 2 weeks.[51]

Thiotepa has the shortest t1/2 among the drugs used for IT therapy. Its CSF clearance occurs within 4 h. The pharmacologic advantage of IT thiotepa has been debated because of the rapid transcapillary movement of the drug.[52]

Combination IT chemotherapy has no advantage in solid tumor-related LM but adds to toxicity.[12] The cytologic response rate and median survival were similar in a single randomized controlled trial which compared IT MTX plus Ara-C and hydrocortisone (triple IT therapy); there was added toxicity in the combination arm. [Table 5] shows the summary of intrathecal therapies used for LM.[53]
Table 5: Summary of the intrathecal agents used is provided in the table below

Click here to view


Adverse events

Aseptic or chemical meningitis is a commonly observed complication in intra-CSF therapy. It is indicated by clinical symptoms and signs of meningitis as well as sterile CSF pleocytosis.[54] The symptoms of this complication can generally be treated using corticosteroids and intravenous hydration. Quality of life studies have never been done with IT therapy.[9] It is observed in 8%–24% cases receiving intra-CSF therapy.[55]

Other known complications of intra-CSF chemotherapy include seizures, myelopathy, leukoencephalopathy and inadvertent subdural or epidural delivery of the drug (if administered by lumbar puncture). Myelosuppression is also displayed by up to 18% of patients, irrespective of the method of administration.[54]

The use of prophylactic antibiotics (either IT or oral) is not recommended as per existing guidelines.

Systemic therapy

There is a break of the BBB in the setting of LM; therefore, it has been established that several chemotherapies achieve therapeutic levels in the CSF when administered systemically in this setting. Another advantage of systemic chemotherapy is that it does not depend on CSF flow for its action. It penetrates bulky disease and additionally acts on any systemically active or progressive disease. The choice of systemic chemotherapy should be guided by the type of malignancy. Options include high-dose methotrexate (more than 3 g/m 2), high-dose cytarabine (3 g/m 2), capecitabine, thiotepa, and temozolomide.[4],[12]

Targeted therapy

In melanoma, vemurafenib [56] and dabrafenib [57] in BRAF-positive patients with LM disease (LMD) demonstrated significant improvement in clinical symptoms and long-term stabilization of LMD, with survival times >18 months. The median survival of patients treated with a BRAF inhibitor combined with CTLA-4 target was 21.7 weeks, with a range of 2–235 weeks in a Randomized Controlled Trial conducted. The 14 patients who were treated with BRAF inhibitors alone had a median survival of 24.9 weeks.[57],[58]

The arrival of epidermal growth factor receptor (EGFR) mutations and drugs that target them has proven to be a positive advancement in the treatment of LMD secondary to non-small cell lung cancer (NSCLC) because these patients show elevated response rates to TKIs, leading to improved progression-free survival rates.[59],[60] The pulsatile dosing of erlotinib at a rate of 1500 mg once weekly has been shown to reach therapeutic levels within the CSF with reported survival ranging from 2.9 months to continued survival past the study report (>25.4 months.[61],[62] Third-generation TKIs (e.g., Osimertinib) show promising results because of their increased CNS permeability and ability to reach high concentrations in the CSF. In the BLOOM study, Osimertinib was given at a dose of 160 mg to 41 patients with LM from EGFR-mutated advanced NSCLC whose disease had progressed on EGFR-TKI therapy. Meaningful improvements were obtained in terms of radiologic response, symptomatic improvement, CSF clearance of malignant cells, and there was a manageable toxicity profile in all patients.[63],[64] The second-generation ALK inhibitors, namely ceritinib and alectinib, have shown better CNS activity in several case reports of patients with crizotinib ( first-generation ALK inhibitor) resistant disease.[65] Phase 2 clinical trial is under way to study the efficacy of ceritinib in treating patients with LM in ALK-rearranged NSCLC.[65],[66]

Intrathecal trastuzumab administration has been found to be effective in LM from HER2-positive breast cancer.[67],[68] A phase I trial of IT has demonstrated that it is well tolerated, and many phase II clinical trials are underway to prove efficacy and confirm toxicity.[9] The LANDSCAPE trial of HER2-positive breast cancer patients with brain metastases (which included LM metastases) with the use of combination of capecitabine and lapatinib (both oral drugs) has shown an amazing response rate of 65.9%.[69]

Newer therapeutic approaches

Safety and efficacy of IT (via Ommaya reservoir) and intravenous nivolumab combination has been tried in combination in single center Phase I/Ib trial and has shown great promise.[70] A dose of 20 mg nivolumab is the recommended dose.

Combinations of chemotherapy with anti-vascular endothelial growth factor inhibitors (bevacizumab) and EGFR monoclonal antibodies (cetuximab) are also being tried and has shown to be safe.[1]

Abemaciclib, a CDK 4/6 inhibitor, is currently being used in a phase 2 clinical trial of patients with LM from NSCLC and breast cancer [71] and results are awaited.

Radiation therapy

The only mode of radiotherapy that treats the entire neurological milieu is craniospinal axis irradiation. It could help in relief of pain and re-establish normal CSF flow. However, problems associated with it include:

  1. Most of the patients have some neuraxial region previously irradiated
  2. Prior cytotoxic chemotherapy may have led to poor bone marrow reserve in several patients
  3. They may have poor bone marrow store because of exposure to cytotoxic chemotherapy
  4. It rarely leads to neurological recovery
  5. Retrospective studies in patients with breast and lung cancers showed that radiation is unlikely to improve survival.


Hence this modality is less commonly advocated in clinical practice.[4]

Surgery

Surgical procedures are usually instituted in cases of:

  1. Raised intracranial pressure (with symptomatic hydrocephalus) requiring ventriculoperitoneal shunting (VPS)
  2. Placement of ventricular access device to facilitate intra-CSF drug treatment
  3. Rarely for meningeal biopsy.


VPS could provide relief of symptoms and the performance status. This will allow the treating physician to propose more systemic treatments in a multidisciplinary clinic.[4],[72]

Symptomatic care

Supportive care is especially significant for patients with LM because the quality of life mostly deteriorated. Steroids should be utilized sparingly but effectively, that is, it should be prescribed at the lowest dose and for the shortest time possible to prevent steroid related adverse events. Special care should be taken to manage seizures taking into consideration the interactions with systemic treatments. The need for psycho-oncological support for the patient and caregiver should be studied.[3] Psychostimulants could be used to mitigate fatigue related to treatment, specifically radiation. Palliative focal radiation, opioids, or opioid-sparing agents is useful to control pain due to cranial and spinal nerve involvement. Unfortunately, this is often refractory if the response to treatment of the underlying disease is poor.[9]


  Conclusion Top


The management of leptomeningeal metastases should be done on a case-by-case basis. A multidisciplinary approach should be undertaken. The primary sites of tumor and its systemic treatment options as well as clinical/imaging findings and cytological positivity of leptomeningeal metastases should guide the treatment and its response. The histology and molecular characteristics of the malignancy should be considered for modifying the systemic treatment. Despite advances in the cancer diagnosis and treatment field, LM remains one of the most 'difficult to manage' complications of cancer; more so as the occurrence of LM is increasing with advancement of cancer treatment. The complexity in diagnosis, poor prognosis, the calamitous impact on quality of life, and diverse response to standard cancer-directed therapies are the main obstacles in the management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.[74]



 
  References Top

1.
Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol 2018;19:e43-55.  Back to cited text no. 1
    
2.
Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol 2006;5:443-52.  Back to cited text no. 2
    
3.
Le Rhun E, Preusser M, van den Bent M, Andratschke N, Weller M. How we treat patients with leptomeningeal metastases. ESMO Open 2019;4:e000507.  Back to cited text no. 3
    
4.
Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 2013;4:S265-88.  Back to cited text no. 4
    
5.
Norris LK, Grossman SA, Olivi A. Neoplastic meningitis following surgical resection of isolated cerebellar metastasis: A potentially preventable complication. J Neurooncol 1997;32:215-23.  Back to cited text no. 5
    
6.
Elliott JP, Keles GE, Waite M, Temkin N, Berger MS. Ventricular entry during resection of malignant gliomas: effect on intracranial cerebrospinal fluid tumor dissemination. J Neurosurg 1994;80:834-9.  Back to cited text no. 6
    
7.
Le Rhun E, Taillibert S, Zairi F, Devos P, Pierret MF, Dubois F, et al. Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: A case-control study. J Neurooncol 2011;105:309-15.  Back to cited text no. 7
    
8.
Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: High incidence of central nervous system metastases. Cancer 2008;113:2638-45.  Back to cited text no. 8
    
9.
Wang N, Bertalan MS, Brastianos PK. Leptomeningeal metastasis from systemic cancer: Review and update on management. Cancer 2018;124:21-35.  Back to cited text no. 9
    
10.
Waki F, Ando M, Takashima A, Yonemori K, Nokihara H, Miyake M, et al. Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors. J Neurooncol 2009;93:205-12.  Back to cited text no. 10
    
11.
Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients. Cancer 1982;49:759-72.  Back to cited text no. 11
    
12.
Taillibert S, Chamberlain MC. Leptomeningeal metastasis. Handb Clin Neurol 2018;149:169-204.  Back to cited text no. 12
    
13.
Kokkoris CP. Leptomeningeal carcinomatosis. How does cancer reach the pia-arachnoid? Cancer 1983;51:154-60.  Back to cited text no. 13
    
14.
Gonzalez-Vitale JC, Garcia-Bunuel R. Meningeal carcinomatosis. Cancer 1976;37:2906-11.  Back to cited text no. 14
    
15.
Boyle R, Thomas M, Adams JH. Diffuse involvement of the leptomeninges by tumour-a clinical and pathological study of 63 cases. Postgrad Med J 1980;56:149-58.  Back to cited text no. 15
    
16.
Kölmel HW. Cytology of neoplastic meningosis. J Neurooncol 1998;38:121-5.  Back to cited text no. 16
    
17.
Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): The meaning of a positive CSF cytology. Neurology 1979;29:1369-75.  Back to cited text no. 17
    
18.
Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, et al. Cerebrospinal fluid cytology in patients with cancer: Minimizing false-negative results. Cancer 1998;82:733-9.  Back to cited text no. 18
    
19.
Chamberlain MC, Kormanik PA, Glantz MJ. A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro Oncol 2001;3:42-5.  Back to cited text no. 19
    
20.
DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998;38:245-52.  Back to cited text no. 20
    
21.
Schold SC, Wasserstrom WR, Fleisher M, Schwartz MK, Posner JB. Cerebrospinal fluid biochemical markers of central nervous system metastases. Ann Neurol 1980;8:597-604.  Back to cited text no. 21
    
22.
Le Rhun E, Massin F, Tu Q, Bonneterre J, Bittencourt Mde C, Faure GC. Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis. BMC Clin Pathol 2012;12:21.  Back to cited text no. 22
    
23.
Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013;80:1598-605.  Back to cited text no. 23
    
24.
Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, et al. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol 2016;34:2404-15.  Back to cited text no. 24
    
25.
Glantz MJ, Hall WA, Cole BF, Chozick BS, Shannon CM, Wahlberg L, et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer 1995;75:2919-31.  Back to cited text no. 25
    
26.
Chamberlain MC, Kormanik PA. Prognostic significance of 111indium-DTPA CSF flow studies in leptomeningeal metastases. Neurology 1996;46:1674-7.  Back to cited text no. 26
    
27.
Trump DL, Grossman SA, Thompson G, Murray K. CSF infections complicating the management of neoplastic meningitis. Clinical features and results of therapy. Arch Intern Med 1982;142:583-6.  Back to cited text no. 27
    
28.
Chamberlain MC. Radioisotope CSF flow studies in leptomeningeal metastases. J Neurooncol 1998;38:135-40.  Back to cited text no. 28
    
29.
Mason WP, Yeh SD, DeAngelis LM. 111Indium-diethylenetriamine pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases. Neurology 1998;50:438-44.  Back to cited text no. 29
    
30.
Collie DA, Brush JP, Lammie GA, Grant R, Kunkler I, Leonard R, et al. Imaging features of leptomeningeal metastases. Clin Radiol 1999;54:765-71.  Back to cited text no. 30
    
31.
Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999;246:810-4.  Back to cited text no. 31
    
32.
Freilich RJ, Krol G, DeAngelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol 1995;38:51-7.  Back to cited text no. 32
    
33.
Beauchesne P. Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. Lancet Oncol 2010;11:871-9.  Back to cited text no. 33
    
34.
Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ. Leptomeningeal metastasis: Clinical experience of 519 cases. Eur J Cancer 2016;56:107-14.  Back to cited text no. 34
    
35.
National Comprehensive Cancer Network. Central Nervous System Cancers. Fort Washington, PA: National Comprehensive Cancer Network; 2019.  Back to cited text no. 35
    
36.
Chamberlain MC, Glantz M, Groves MD, Wilson WH. Diagnostic tools for neoplastic meningitis: Detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol 2009;36:S35-45.  Back to cited text no. 36
    
37.
Taillibert S, Laigle-Donadey F, Chodkiewicz C, Sanson M, Hoang-Xuan K, Delattre JY. Leptomeningeal metastases from solid malignancy: A review. J Neurooncol 2005;75:85-99.  Back to cited text no. 37
    
38.
Oechsle K, Lange-Brock V, Kruell A, Bokemeyer C, de Wit M. Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: A retrospective analysis. J Cancer Res Clin Oncol 2010;136:1729-35.  Back to cited text no. 38
    
39.
Gauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, et al. Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol 2010;21:2183-7.  Back to cited text no. 39
    
40.
Lee S, Ahn HK, Park YH, Nam DH, Lee JI, Park W, et al. Leptomeningeal metastases from breast cancer: Intrinsic subtypes may affect unique clinical manifestations. Breast Cancer Res Treat 2011;129:809-17.  Back to cited text no. 40
    
41.
Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer 2012;76:387-92.  Back to cited text no. 41
    
42.
Chamberlain M, Junck L, Brandsma D, Soffietti R, Rudà R, Raizer J, et al. Leptomeningeal metastases: A RANO proposal for response criteria. Neuro Oncol 2017;19:484-92.  Back to cited text no. 42
    
43.
Chamberlain MC, Kormanik PR. Carcinomatous meningitis secondary to breast cancer: Predictors of response to combined modality therapy. J Neurooncol 1997;35:55-64.  Back to cited text no. 43
    
44.
Chamberlain MC, Kormanik P. Carcinoma meningitis secondary to non-small cell lung cancer: Combined modality therapy. Arch Neurol 1998;55:506-12.  Back to cited text no. 44
    
45.
Boogerd W, van den Bent MJ, Koehler PJ, Heimans JJ, van der Sande JJ, Aaronson NK, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: A randomised study. Eur J Cancer 2004;40:2726-33.  Back to cited text no. 45
    
46.
Bokstein F, Lossos A, Siegal T. Leptomeningeal metastases from solid tumors: A comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy. Cancer 1998;82:1756-63.  Back to cited text no. 46
    
47.
Shapiro WR, Young DF, Mehta BM. Methotrexate: Distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975;293:161-6.  Back to cited text no. 47
    
48.
Shapiro WR, Posner JB, Ushio Y, Chemik NL, Young DF. Treatment of meningeal neoplasms. Cancer Treat Rep 1977;61:733-43.  Back to cited text no. 48
    
49.
de Azevedo CR, Cruz MR, Chinen LT, Peres SV, Peterlevitz MA, de Azevedo Pereira AE, et al. Meningeal carcinomatosis in breast cancer: Prognostic factors and outcome. J Neurooncol 2011;104:565-72.  Back to cited text no. 49
    
50.
Clatot F, Philippin-Lauridant G, Ouvrier MJ, Nakry T, Laberge-Le-Couteulx S, Guillemet C, et al. Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy. J Neurooncol 2009;95:421-6.  Back to cited text no. 50
    
51.
Esteva FJ, Soh LT, Holmes FA, Plunkett W, Meyers CA, Forman AD, et al. Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 2000;46:382-6.  Back to cited text no. 51
    
52.
Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol 1993;11:561-9.  Back to cited text no. 52
    
53.
Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987;5:1655-62.  Back to cited text no. 53
    
54.
Chamberlain MC, Kormanik PA, Barba D. Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 1997;87:694-9.  Back to cited text no. 54
    
55.
Chamberlain MC. Leptomeningeal metastasis. Semin Neurol 2010;30:236-44.  Back to cited text no. 55
    
56.
Schäfer N, Scheffler B, Stuplich M, Schaub C, Kebir S, Rehkämper C, et al. Vemurafenib for leptomeningealmelanomatosis. J Clin Oncol 2013;31:e173-4.  Back to cited text no. 56
    
57.
Simeone E, De Maio E, Sandomenico F, Fulciniti F, Lastoria S, Aprea P, et al. Neoplastic leptomeningitis presenting in a melanoma patient treated with dabrafenib (a V600EBRAF inhibitor): A case report. J Med Case Rep 2012;6:131.  Back to cited text no. 57
    
58.
Geukes Foppen MH, Brandsma D, Blank CU, van Thienen JV, Haanen JB, Boogerd W. Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol 2016;27:1138-42.  Back to cited text no. 58
    
59.
Thomas KH, Ramirez RA. Leptomeningeal disease and the evolving role of molecular targeted therapy and immunotherapy. Ochsner J 2017;17:362-78.  Back to cited text no. 59
    
60.
How J, Mann J, Laczniak AN, Baggstrom MQ. Pulsatile erlotinib in EGFR-positive non-small-cell lung cancer patients with leptomeningeal and brain metastases: Review of the literature. Clin Lung Cancer 2017;18:354-63.  Back to cited text no. 60
    
61.
Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.  Back to cited text no. 61
    
62.
Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010;99:283-6.  Back to cited text no. 62
    
63.
Ahn MJ, Kim DW, Kim TM, Lin CC, Ratnayake J, Carlie DJ, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-smallcell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). J ClinOncol 2016;34 suppl 15:9003.  Back to cited text no. 63
    
64.
Yang JC, Cho BC, Kim DW, Kim SW, Lee JS, Su WC, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study. J Clin Oncol 2017;35:2020.  Back to cited text no. 64
    
65.
Gainor JF, Sherman CA, Willoughby K, Logan J, Kennedy E, Brastianos PK, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 2015;10:232-6.  Back to cited text no. 65
    
66.
Ou SH, Sommers KR, Azada MC, Garon EB. Alectinib induces a durable (and amp; gt; 15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis. Oncologist 2015;20:224-6.  Back to cited text no. 66
    
67.
Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lässig D, et al. Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Oncol Rep 2006;15:1373-7.  Back to cited text no. 67
    
68.
Zagouri F, Sergentanis TN, Bartsch R, Berghoff AS, Chrysikos D, de Azambuja E, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: A systematic review and pooled analysis. Breast Cancer Res Treat 2013;139:13-22.  Back to cited text no. 68
    
69.
Bachelot T, Romieu G, Campone M, Diéras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol 2013;14:64-71.  Back to cited text no. 69
    
70.
Glitza IC, Rohlfs ML, Iqbal M, Richard J, Burton E, Duncan S, et al. 1301TiP-A phase I/Ib study of concurrent intravenous (IV) and intrathecal (IT) nivolumab (Nivo) for melanoma patients (pts) with leptomeningeal disease (LMD). Ann Oncol 2018;29 (Suppl 8).  Back to cited text no. 70
    
71.
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov 2016;6:740-53.  Back to cited text no. 71
    
72.
Chaul-Barbosa C, Morikawa A, Patil S, Boire A, Jordan L, Rozner R, et al. Treatment options of long term survivors with leptomeningeal metastases and breast cancer. Neuro Oncol 2016;18 Suppl 6:Vi33.  Back to cited text no. 72
    
73.
Glantz MJ, Jaeckle KA, Chamberlain MC, Phuphanich S, Recht L, Swinnen LJ, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5:3394-402.  Back to cited text no. 73
    
74.
Shapiro WR, Schmid R, Glantz M, Miller JJ. A randomized phase III/ IV study to determine benefit and safety of cytarabine liposome injection for treatment of neoplastic meningitis. J Clin Oncol 2006;24:1528.  Back to cited text no. 74
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Methods
Results and Disc...
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed87    
    Printed0    
    Emailed0    
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal